In the past 20 years, it has become apparent that inflammation is a fundamental driver of WHO Group 1 pulmonary arterial hypertension (PAH), in such diverse etiologies as idiopathic, collagen vascular disease- associated (CVD-PAH), and infection-associated disease, notably of schistosomiasis-associated PAH, and Group 3 COPD-related pulmonary hypertension (PH). Our work has delineated the upstream role of Type 2 inflammation triggered by Schistosoma eggs in the lung circulation, leading to TGF-? production, which drives subsequent pulmonary vascular remodeling and PH in Schistosoma-induced PH. Specifically, Project 2 addresses the key role of TH2 inflammation, leading to macrophage activation of TGF-?, as the bridge between Type 2 inflammation and molecular effectors of pulmonary vascular remodeling. Building on extensive and innovative experimental and human studies, Project 2 complements the insights into STAT3-driven hypoxia-driven stimuli in Project 1; furthermore, with Project 3, we expand on the role of leukotriene B4 (LTB4) in Schistosoma-PH. Our work is novel not only in regards to linking inflammation and pulmonary hypertension, but also in leveraging the importance of schistosomiasis as the third most common parasitic disease worldwide, and one of the most common causes of WHO Group 1 PAH, affecting approximately 5-15 million people predominantly in Africa and Brazil, with a similar spectrum of pulmonary vascular lesions as IPAH and CVD-PAH. We propose that schistosomiasis-induced Type 2 immune responses trigger TGF-?1 synthesis and activation by macrophages, via the direction action of macrophage-derived thrombospondin (TSP-1). Active TGF-?1 then causes metabolic reprogramming of vascular cells, resulting in pulmonary vascular remodeling and pulmonary hypertension. Our specific aims are: Aim 1: To determine that the Type 2 inflammatory mediators IL-4 and IL-13 drive pro-vascular remodeling macrophages. Aim 2: To determine that IL-4/IL-13-stimulated macrophages induce vascular remodeling by TGF-?1 activation via direct interaction with TSP-1. Aim 3: To determine that macrophage-driven TGF-?1 causes metabolic reprogramming in pulmonary vascular cells in Schistosoma-induced PH. This proposal relies on the integration of genetically modified mouse models of Schistosoma-PH with parallel analysis of diseased human lung tissue, including both Schistosoma- and scleroderma-associated PAH. Complementary and synergistic lines of investigations are proposed to determine if key mechanistic elements of Project 2 also are also pertinent in Projects 1 (specifically the roles of adventitia fibroblasts and STAT- specific macrophages populations) and 3 (proremodeling action of LTB4). Focused retrospective studies aimed at targets of Type 2 inflammation are leveraged with Clinical Core B to translate key findings into PAH patients.